Gentamicin Pharmacokinetics and Monitoring in Pediatric Febrile Neutropenic Patients

Bialkowski, Sabina; Staatz, C. E.; Clark, Julia; Lawson, Rachael; Hennig, Stefanie

doi:10.1097/ftd.0000000000000341

Cited by 10 publications

(13 citation statements)

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“…In the first study (8), typical CL values of 9.33 liters/h/70 kg and 10.3 liters/h/70 kg were reported in pediatric patients receiving and not receiving chemotherapy, respectively. In the second study (10), a typical CL of 8.10 liters/h/70 kg was reported. Comparison of the CL values of gentamicin obtained in this study with the values published in the literature is difficult because most previous studies were primarily based on neonates or infants and involved different analysis techniques.…”

Section: Discussionmentioning

confidence: 99%

“…The typical gentamicin apparent CL (CL/F) in these children (7.21 liters/h/70 kg for a patient with an average Scr of 33.0 mol/liter) was higher than that estimated in this study based on intravenous administration (5.77 liters/h/70 kg for a patient with an average Scr of 37.4 mol/liter). Two studies have been performed in pediatric oncology patients, but they used noncompartmental analysis methods (8,10). In the first study (8), typical CL values of 9.33 liters/h/70 kg and 10.3 liters/h/70 kg were reported in pediatric patients receiving and not receiving chemotherapy, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…Previous pharmacokinetic studies using noncompartmental pharmacokinetic analysis suggested gentamicin starting doses of between 7.5 and 10.8 mg/kg of body weight for pediatric oncology patients (8,10,29). While exposure targets have not been fully elucidated in this population, guidelines typically recommend that an area under the concentration-time curve from time zero to 24 h (AUC 24 )-to-bacterial MIC ratio (AUC 24 /MIC) of between 80 and 100 and/or a maximum concentration (C max )-to-MIC ratio (C max /MIC) of greater than 10 be targeted (30,31).…”

Section: Figmentioning

confidence: 99%

“…After implementation of the model in a Bayesian forecasting program, future studies should focus on evaluating its clinical applicability to personalize gentamicin dosing regimens, ability to reduce the frequency of blood sampling during TDM, and capacity to improve target attainment compared to current practice in pediatric oncology patients (10).…”

Section: Figmentioning

confidence: 99%

“…Increased clearance (CL) and an increased volume of distribution (V) for gentamicin have been seen in adults (7) and pediatric patients (8,10) with cancer. Augmented renal clearance, possibly due to systemic inflammation, has also been reported in febrile neutropenic patients (11).…”

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A Population Pharmacokinetic Model of Gentamicin in Pediatric Oncology Patients To Facilitate Personalized Dosing

Llanos-Paez

Staatz

Lawson

et al. 2017

Antimicrob Agents Chemother

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To ensure the safe and effective dosing of gentamicin in children, therapeutic drug monitoring (TDM) is recommended. TDM utilizing Bayesian forecasting software is recommended but is unavailable, as no population model that describes the pharmacokinetics of gentamicin in pediatric oncology patients exists. This study aimed to develop and externally evaluate a population pharmacokinetic model of gentamicin to support personalized dosing in pediatric oncology patients. A nonlinear mixed-effect population pharmacokinetic model was developed from retrospective data. Data were collected from 423 patients for model building and a further 52 patients for external evaluation. A two-compartment model with first-order elimination best described the gentamicin disposition. The final model included renal function (described by fat-free mass and postmenstrual age) and the serum creatinine concentration as covariates influencing gentamicin clearance (CL). Final parameter estimates were as follow CL, 5.77 liters/h/70 kg; central volume of distribution, 21.6 liters/70 kg; peripheral volume of distribution, 13.8 liters/70 kg; and intercompartmental clearance, 0.62 liter/h/70 kg. External evaluation suggested that current models developed in other pediatric cohorts may not be suitable for use in pediatric oncology patients, as they showed a tendency to overpredict the observations in this population. The final model developed in this study displayed good predictive performance during external evaluation (root mean square error, 46.0%; mean relative prediction error, Ϫ3.40%) and may therefore be useful for the personalization of gentamicin dosing in this cohort. Further investigations should focus on evaluating the clinical application of this model. KEYWORDS pharmacokinetics, gentamicin, NONMEM, pediatrics, oncology, pharmacometrics, population pharmacokinetics F ebrile neutropenia induced by chemotherapy is a common complication in pediatric oncology patients. Neutropenic patients are more susceptible to the development of infections (1). Sepsis is the primary cause of mortality and morbidity in pediatric oncology patients with febrile neutropenia (2). The rate of mortality due to sepsis is 1.6-fold higher for oncology pediatric patients than it is for other pediatric patients (3). Aminoglycoside antibiotics, such as gentamicin, in combination with other broad-spectrum antibacterial agents play an important role in managing infectious complications in these individuals and are used as second-line therapies when treating Gram-negative bacterial infections and when resistance to first-line agents develops (4).Gentamicin has a narrow therapeutic window and displays large pharmacokinetic variability. High levels of and prolonged exposure to gentamicin has been associated with nephro-and ototoxicity (5, 6). Pediatric oncology patients often receive long

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

A Population Pharmacokinetic Model of Gentamicin in Pediatric Oncology Patients To Facilitate Personalized Dosing

Llanos-Paez

Staatz

Lawson

et al. 2017

Antimicrob Agents Chemother

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Antimicrobial stewardship in paediatric oncology: Impact on optimising gentamicin use in febrile neutropenia

Hennig

Staatz

Natanek

et al. 2017

Pediatric Blood & Cancer

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Clinical Pharmacokinetics of Gentamicin in Various Patient Populations and Consequences for Optimal Dosing for Gram-Negative Infections: An Updated Review

et al. 2022

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Gentamicin is an aminoglycoside antibiotic with a small therapeutic window that is currently used primarily as part of shortterm empirical combination therapy. Gentamicin dosing schemes still need refinement, especially for subpopulations where pharmacokinetics can differ from pharmacokinetics in the general adult population: obese patients, critically ill patients, paediatric patients, neonates, elderly patients and patients on dialysis. This review summarizes the clinical pharmacokinetics of gentamicin in these patient populations and the consequences for optimal dosing of gentamicin for infections caused by Gram-negative bacteria, highlighting new insights from the last 10 years. In this period, several new population pharmacokinetic studies have focused on these subpopulations, providing insights into the typical values of the most relevant pharmacokinetic parameters, the variability of these parameters and possible explanations for this variability, although unexplained variability often remains high. Both dosing schemes and pharmacokinetic/pharmacodynamic (PK/PD) targets varied widely between these studies. A gentamicin starting dose of 7 mg/kg based on total body weight (or on adjusted body weight in obese patients) appears to be the optimal strategy for increasing the probability of target attainment (PTA) after the first administration for the most commonly used PK/PD targets in adults and children older than 1 month, including critically ill patients. However, evidence that increasing the PTA results in higher efficacy is lacking; no studies were identified that show a correlation between estimated or predicted PK/PD target attainment and clinical success. Although it is unclear if performing therapeutic drug monitoring (TDM) for optimization of the PTA is of clinical value, it is recommended in patients with highly variable pharmacokinetics, including patients from all subpopulations that are critically ill (such as elderly, children and neonates) and patients on intermittent haemodialysis. In addition, TDM for optimization of the dosing interval, targeting a trough concentration of at least < 2 mg/L but preferably < 0.5-1 mg/L, has proven to reduce nephrotoxicity and is therefore recommended in all patients receiving more than one dose of gentamicin. The usefulness of the daily area under the plasma concentration-time curve for predicting nephrotoxicity should be further investigated. Additionally, more research is needed on the optimal PK/PD targets for efficacy in the clinical situations in which gentamicin is currently used, that is, as monotherapy for urinary tract infections or as part of short-term combination therapy.

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Gentamicin Pharmacokinetics and Monitoring in Pediatric Febrile Neutropenic Patients

Abstract: Based on a log-linear method of analysis, current dosing appears to be consistently producing gentamicin exposure below pre-defined pharmacokinetic targets, suggesting that an increase in the recommended starting dose of gentamicin may be required.

Cited by 10 publications

References 0 publications

A Population Pharmacokinetic Model of Gentamicin in Pediatric Oncology Patients To Facilitate Personalized Dosing

A Population Pharmacokinetic Model of Gentamicin in Pediatric Oncology Patients To Facilitate Personalized Dosing

Antimicrobial stewardship in paediatric oncology: Impact on optimising gentamicin use in febrile neutropenia

Clinical Pharmacokinetics of Gentamicin in Various Patient Populations and Consequences for Optimal Dosing for Gram-Negative Infections: An Updated Review

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